A study was made of the role of natural killer cells (NK) against the Madison lung carcinoma in BALB/c mice. NK-enriched nude spleen cell suspensions had little effect against Madison tumor cells in short-term 51 Chromium-release assay. Modest NK activity could be detected in longer assays, however, and reached high levels at 36 hours in the presence of interferon. These same macrophage-depleted, NK-enriched spleen cells had little growth inhibitory effect during co-culture with Madison tumor cells but became strongly growth inhibitory against Madison cells in the presence of interferon. The addition of small numbers of macrophages to culture of NK-enriched spleen cells and Madison tumor cells was also observed to result in marked augmentation of NK activity and synergistic inhibition of Madison growth.